The present invention relates to novel substituted imidazole compounds having valuable pharmacological properties, especially against inflammatory diseases and allergic conditions. Compounds of this invention are antagonists of the histamine receptors. Some are antagonists of the histamine-H1 receptors. Some are antagonists of the histamine-H3 receptors. Some are antagonists of both the H1 and H3 receptors, in other words dual H1 and H3 receptor antagonists.
The histamine receptors, H1, H2 and H3 are well-identified forms. The H1 receptors are those that mediate the response antagonized by conventional antihistamines. H1 receptors are present, for example, in the ileum, the skin, and the bronchial smooth muscle of humans and other mammals. A well known antagonist of H1 receptors is loratadine, commercially available under the tradename CLARITIN(copyright) from Schering-Plough Corporation, Madison, N.J. Through H2 receptor-mediated responses, histamine stimulates gastric acid secretion in mammals and the chronotropic effect in isolated mammalian atria.
H3 receptor sites are found on sympathetic nerves, where they modulate sympathetic neurotransmission and attenuate a variety of end organ responses under control of the sympathetic nervous system. Specifically, H3 receptor activation by histamine attenuates nonepinephrine outflow to resistance and capacitance vessels, causing vasodilatation.
U.S. Pat. No. 4,767,778 (Arrang et al.) discloses certain imidazoles that behave as agonists of the H3 receptors in rat brain. European Patent Application No. 0 420 396 A2 (Smith Kline and French Laboratories Limited) and Howson et al. (Bioorg. and Med. Chem. Letters, (1992), Vol. 2 No.1, pages 77-78) describe imidazole derivatives having an amidine group as H3 agonists. Van der Groot et al. (Eur. J. Med. Chem. (1992) Vol. 27, pages 511-517) describe isothiourea analogs of histamine as potent agonists or antagonists of the histamine-H3 receptor, and these isothiourea analogs of histamine overlap in part with those of the two references cited above. Clapham et al.. [xe2x80x9cAbility of Histamine-H3 Receptor Antagonists to Improve Cognition and to Increase Acetylcholine Release in vivo in the Ratxe2x80x9d, British Assn. for Psychopharmacology, Jul. 25-28 (1993), reported in J. Psychopharmacol. (Abstr. Book), A17] describe the ability of histamine-H3 receptor antagonists to improve cognition and to increase release of acetylcholine in vivo in the rat. Clapham et al.. [xe2x80x9cAbility of the selective Histamine-H3 Receptor Antagonist Thioperamide to improve Short-term Memory and Reversal Learning in the Ratxe2x80x9d, Brit. J. Pharm. Suppl., 1993, 110, Abstract 65P] present results showing that thioperamide can improve short-term memory and reversal learning in the rat and implicate the involvement of H3 receptors in the modulation of cognitive function. Yokoyama et al.. [xe2x80x9cEffect of Thioperamide, a Histamine-H3 Receptor Antagonist, on Electrically Induced Convulsions in Micexe2x80x9d, Eur. J. Pharmacol., (1993), Vol. 234, pages 129-133] report how thioperamide decreased the duration of each phase of convulsion and raised the electroconvulsive threshold, and go on to suggest that these and other findings support the hypothesis that the central histaminergic system is involved in the inhibition of seizures. International Patent Publication No. WO 9301812-A1 (SmithKline Beecham PLC) describes the use of S-[3-(4(5)-imidazolyl)propyl]isothiourea as a histamine-H3 antagonist, especially for treating cognitive disorders, e.g. Alzheimer""s disease and age-related memory impairment. Schlicker et al. [xe2x80x9cNovel Histamine-H3 Receptor Antagonists: Affinities in an H3 Receptor Binding Assay and Potencies in Two Functional H3 Receptor Modelsxe2x80x9d, British J. Pharmacol., (1994), Vol.112,1043-1048] describe a number of imidazolylalkyl compounds wherein the imidazolylalkyl group is bonded to a guanidine group, an ester group, an amide group, a thioamide group and a urea group, and compared these to thioperamide. Leurs et al. [xe2x80x9cThe Histamine-H3-receptor: A Target for Developing New Drugsxe2x80x9d, Progr. Drug Res. (1992), Vol. 39, pages 127-165] and Lipp et al. [xe2x80x9cPharmacochemistry of H3-receptorsxe2x80x9d in The Histamine Receptor, eds.: Schwartz and Haas, Wiley-Liss, New York (1992), pages 57-72] review a variety of synthetic H3 receptor antagonists, and Lipp et al. (ibid. ) have proposed the necessary structural requirements for an H3 receptor antagonist.
WO 95/14007 claims H3 receptor antagonists of the formula 
wherein A, m, n, R1 and R2 are defined therein. The compounds are disclosed as being useful for treating various disorders, in particular such caused by allergy-induced responses.
WO 93/12093 discloses imidazolylmethyl piperazines and diazepines as H3 antagonists. U.S. patent application, Ser. No. 08/965,754, filed Nov. 7, 1997, discloses imidazolylalkyl substituted heterocyclic ring compounds as H3 receptor antagonists. U.S. patent application, Ser. No. 08/966,344, filed Nov. 7, 1997, discloses phenylalkylimidazoles as H3 receptor antagonists.
WO 96/29315 (PCT/FR96/00432) discloses certain N-imidazolylalkyl compounds containing phenyl moieties attached.
Also disclosing H3 receptor antagonists are: H. Stark et al, Eur. J. of Pharmaceutical Sciences (1995) 3, 95-104; H. Stark et al, J. Med. Chem., (1996) 39, 1157-1163; H. Stark et al, Arch Pharm. Pharm. Med. Chem., (1998) 331, 211-218; and A. Sasse et al, Bioorganic and Medicinal Chem., (2000) 8, 1139-1149.
Reference is also made to J. R. Bagley et al.. Journal of Medicinal Chemistry, (1991), Vol. 34, 827-841, which discloses, among others, N-(imidazolylalkyl) substituted cyclic amine compounds useful as analgesics such as the amine compound with the formula: 
Pending U.S. patent application, Ser. No. 09/173,642, filed Oct. 16, 1998 (R. Wolin et al.), U.S. Pat. No. 6,133,291 discloses N-(imidazolylalkyl) substituted cyclic amine compounds having H3 antagonist activity.
A. Huls et al., Bioorg. and Med.Chem. Letters, 6 (1996), 2013-2018 disclose imidazole compounds containing diphenyl ether moieties as H3 receptor antagonists. The compounds are additionally disclosed to have H1 receptor antagonist activity. An example compound from that publication is: 
where R1 and R2 are defined therein.
A. Buschauer, J. Med. Chem., 32 (1989), 1963-1970 disclose, among others, H2 receptor antagonists of the type: 
where Ar1 and Ar2 may be phenyl and/or pyridyl. EPO 448,765 A1 (published Mar. 30, 1990) discloses neuropeptide-Y antagonist imidazoles of the type: 
where Ar1 and Ar2 may be phenyl and/or pyridyl.
WO 98-58646 (assigned to Novo Nordisk A/S) discloses somatostatin SSTR4 receptor antagonist compounds of the type: 
wherein m is 2-6; n is 1-3; p is 1-6; R1 and R2 are independently H or C1-C6 alkyl optionally substituted with halogen, amino, hydroxy, alkoxy or aryl; X is S, O, NH, NCOPh or N(CN); A is aryl optionally substituted with halogen, amino, hydroxy, nitro, C1-6 alkyl, C1-6 alkoxy, or aryl; and B and D are independently aryl optionally substituted with halogen, amino, hydroxy, C1-6 alkyl, C1-6 alkoxy, or aryl.
Compounds have been reported in the literature as having activity against both H1 and H2 receptors, i.e. dual antagonists against H1 and H2 receptors. Thus, for example, F. Schulze et al., European J. of Pharmaceutical Sciences, 6 (1998), 177-186 report combined H1/H2 receptor antagonists. Other references in this category include F. Schulze et al., Arch Pharm. (Weinheim), 327 (1994), 455-462; C. Wolf et al., Arch Pharm. Med. Chem., 329 (1996), 87-94; and C. Wolf et al., European J. of Pharmaceutical Sciences, 6 (1998), 177-186. Non-imidazole histamine H3 ligands, particularly substituted benzothiazole derivatives as H3 antagonists and H1 blocking activities have been reported by K. Walczynski et al. II Farmaco, 54 (1999), 684-694.
It would be useful to have compounds which are therapeutically effective as antagonists of both the H1 and H3 histamine receptors. The only such reported activity has been through a combination of two different chemical entities, one showing activity against H1 receptors and the other showing activity against H3 receptors. Thus, for example, U.S. Pat. No. 5,869,479 (issued Feb. 9, 1999 to Schering Corporation) discloses the combination of a histamine-H1 receptor antagonist and a histamine-H3 receptor antagonist for the treatment of allergy-induced airway responses.
Pending provisional patent application, Serial No.60/234,039, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to two cyclic moieties via intermediary moiety or moieties at least one of which intermediary moiety or moieties is a cyclic moiety.
Pending provisional patent application, Serial No. 60/234,038, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to a tricyclic moiety via intermediary moiety or moieties which intermediary moiety or moieties are all acyclic moieties.
Pending provisional patent application, Serial No. 60/234,053, filed Sep. 20, 2000, discloses novel imidazole compounds having H3 as well as dual H1 and H3 antagonist activity. The compounds disclosed therein have general formula in which an imidazole is linked to a tricyclic moiety via intermediary moiety or moieties at least one of which intermediary moiety or moieties is a cyclic moiety.
It would be a welcome contribution to the art to have novel substituted imidazole compounds.
It would be useful to have the same chemical entity showing H3 receptor activity as well as dual activity against both H1 and H3 receptors.
It would be useful to have novel substituted imidazoles showing H3 receptor activity as well as dual activity against both H1 and H3 receptors.
This invention provides just such a contribution by providing novel substituted imidazole compounds having dual H1 and H3 antagonist activity.
In one embodiment, this invention provides novel substituted imidazole compounds having H3 antagonist activity as well as dual H1 and H3 antagonist activity. The inventive compounds are substituted imidazoles wherein the imidazole is linked to two cyclic moieties via intermediary moiety or moieties which intermediary moiety or moieties are all acyclic. The compounds have the general structure shown in Formula I, including enantiomers, stereoisomers and tautomers thereof, as well as its pharmaceutically acceptable salts or solvates: 
wherein
G is selected from the group consisting of C1-C6 alkyl or a bond;
M is a moiety selected from the group consisting of xe2x80x94Cxe2x95x90Cxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94C(xe2x95x90NR7)xe2x80x94NR6xe2x80x94, xe2x80x94NR6xe2x80x94C(xe2x95x90NR7)xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94NR6xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94NR6xe2x80x94, xe2x80x94NR6xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94NR6xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NR6xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N30 R6R8xe2x80x94, and 
p is 1-6
V is C1-C6 alkyl;
X and Y may be the same or different and are independently selected from the group consisting of N, CH, or N-oxide, with the proviso that at least one of X and Y is N or N-oxide;
R1 and R2 may each number 1-4 and are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogen, polyhalolower alkyl, xe2x80x94OH, xe2x80x94N(R6)2, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOR6, xe2x80x94CONR6R8, and xe2x80x94NR6xe2x80x94C(O)xe2x80x94R7(wherein R7 is not xe2x80x94OH or xe2x80x94CN);
R3 is selected from hydrogen, lower alkyl, lower alkoxy, hydroxyl, polyhalolower alkyl, and a bond forming a double bond towards the moiety G when G is C1-C6 alkyl;
R4 and R5 are independently selected from the group consisting of hydrogen, lower alkyl, and polyhalolower alkyl;
R6 and R5 are independently selected from hydrogen, lower alkyl, aralkyl, alkylaryl, polyhalolower alkyl, substituted or unsubstituted phenyl; and substituted or unsubstituted benzyl; and
R7 is selected from H, OH, alkoxy, cyano, phenyl, substituted phenyl, benzyl, and substituted benzyl;
with the proviso that when G is a bond and when M is either xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94NR6xe2x80x94, then one of X and Y is N; and with the further proviso that when R3 is xe2x80x94OH or alkoxyl, and G is a bond, then Mxe2x89xa0O or NR6.
When used herein, the following terms have the given meanings:
lower alkyl (including the alkyl portions of lower alkoxy)xe2x80x94represents a straight or branched, saturated hydrocarbon chain having from 1 to 6 carbon atoms, preferably from 1 to 4. The term xe2x80x9calkylxe2x80x9d may also refer to moieties such as alkylenes and related moieties that are chemically suitable. Thus, for example, the definition of G and V may also include moieties such as ethylene, butylenes, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90CH2)xe2x80x94 and the like;
arylxe2x80x94represents a carbocyclic group having from 6 to 14 carbon atoms and having at least one benzenoid ring, with all available substitutable aromatic carbon atoms of the carbocyclic group being intended as possible points of attachment. Preferred aryl groups include 1-naphthyl, 2-naphthyl and indanyl, and especially phenyl and substituted phenyl;
aralkylxe2x80x94represents a moiety containing an aryl group linked to the main group via an intermediary lower alkyl;
alkylarylxe2x80x94represents a moiety containing a lower alkyl linked to the main group via an intermediary aryl group;
cycloalkylxe2x80x94represents a saturated carbocyclic ring having from 3 to 8 carbon atoms, preferably 5 or 6, optionally substituted.
heterocyclicxe2x80x94represents, in addition to the heteroaryl groups defined below, saturated and unsaturated cyclic organic groups having at least one O, S and/or N atom interrupting a carbocyclic ring structure that consists of one ring or two fused rings, wherein each ring is 5-, 6- or 7-membered and may or may not have double bonds that lack delocalized pi electrons, which ring structure has from 2 to 8, preferably from 3 to 6 carbon atoms, e.g., 2- or 3-piperidinyl, 2- or 3-piperazinyl, 2- or 3-morpholinyl, or 2- or 3-thiomorpholinyl;
halogenxe2x80x94represents fluorine, chlorine, bromine and iodine;
heteroarylxe2x80x94represents a cyclic organic group having at least one O, S and/or N atom interrupting a carbocyclic ring structure and having a sufficient number of delocalized pi electrons to provide aromatic character, with the aromatic heterocyclic group having from 2 to 14, preferably 4 or 5 carbon atoms, e.g., 2-, 3- or 4-pyridyl, 2- or 3-furyl, 2- or 3-thienyl, 2-, 4- or 5-thiazolyl, 2- or 4-imidazolyl, 2-, 4- or 5-pyrimidinyl, 2-pyrazinyl, or 3- or 4-pyridazinyl, etc. Preferred heteroaryl groups are 2-, 3- and 4-pyridyl; Such heteroaryl groups may also be optionally substituted.
The term xe2x80x9csubstitutedxe2x80x9d, unless otherwise defined, refers to chemically suitable substitution with moieties such as, for example, alkyl, alkoxy, xe2x80x94CF3, halogen or aryl.
Furthermore, the term xe2x80x9calkylxe2x80x9d, when chemically suitable, also includes alkylene and related moieties. Thus, for example, the above-described definitions for G and V, could also include moieties such as, for example, ethylene, butylene, xe2x80x94CH2xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH2xe2x80x94C(xe2x95x90CH2)xe2x80x94, and the like.
Also included in the invention are tautomers, enantiomers and other optical isomers of compounds of Formula I, as well as pharmaceutically acceptable salts and solvates thereof.
A further feature of the invention is pharmaceutical compositions containing as active ingredient a compound of Formula I (or its salt, solvate or isomers) together with a pharmaceutically acceptable carrier or excipient.
The invention also provides methods for preparing compounds of Formula I, as well as methods for treating diseases such as, for example, inflammation, allergy, diseases of the GI-tract, cardiovascular disease, or disturbances of the central nervous system as well as allergy-induced airway (e.g., upper airway) responses, decongestion and obesity. The methods for treating comprise administering to a mammalian patient (including humans and animals) suffering from said disease or diseases a therapeutically effective amount of a compound of Formula I, or pharmaceutical compositions comprising a compound of Formula I.
In one embodiment, the present invention provides novel imidazole compounds of Formula I: 
where the various symbols are as defined above. Representative compounds of the invention which exhibit excellent H3 antagonist activity are listed below. 
Some examples of compounds exhibiting both (or dual) H1 and H3 activity include: 
The compounds of the invention are basic and form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for such salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their corresponding salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their corresponding free base forms for purposes of this invention.
Depending upon the substituents on the inventive compounds, one may be able to form salts with bases too. Thus, for example, if there are carboxylic acid substituents in the molecule, salts may be formed with inorganic as well as organic bases such as, for example, NaOH, KOH, NH4OH, tetraalkylammonium hydroxide, and the like.
As stated earlier, the invention includes tautomers, enantiomers and other stereoisomers of the compounds also. Thus, as one skilled in the art knows, certain imidazole compounds may exist in tautomeric forms. Such variations are contemplated to be within the scope of the invention.
Another embodiment of the invention discloses a method of making the substituted imidazoles disclosed above. The compounds may be prepared by several processes well known in the art. In one method, the imidazole part (designated xe2x80x9cthe left side componentxe2x80x9d herein for simplicity purposes; see example below): 
and the diaryl part (designated xe2x80x9cthe right side componentxe2x80x9d herein for simplicity purposes; see example below): 
may be prepared separately. The left side component and the right side component may contain reactive moieties attached to them; these reactive moieties on the two components are suitable to be reacted with each other under appropriate reaction conditions. Thus, for example, the left side component may contain a carboxylic acid, and the right side component may have an amine end. Under appropriate reaction conditions, the two components may be reacted together whereby an imidazole containing a diaryl alkyl moiety linked through an extended amide chain is obtained. Other substituted imidazoles may similarly be prepared.
Isolation of the compound at various stages of the reaction may be achieved by standard techniques such as, for example, filtration, evaporation of solvent and the like. Purification of the product, intermediate and the like, may also be performed by standard techniques such as recrystallization, distillation, sublimation, chromatography, conversion to a suitable derivative which may be recrystallized and converted back to the starting compound, and the like. Such techniques are well known to those skilled in the art.
The thus prepared compounds may be analyzed for their composition and purity as well as characterized by standard analytical techniques such as, for example, elemental analysis, NMR, mass spectroscopy, and IR spectra.
The inventive compounds can readily be evaluated to determine activity at both H1 and H3 receptors by known methods, such as, for example, E. A. Brown et al, British J. Pharm., (1986) Vol. 80, 569. H3 activity may be determined by, for example, the guinea pig brain membrane assay and the guinea pig neuronal ileum contraction assay, both of which are described in U.S. Pat. No. 5,352,707. Another useful assay for H3 activity utilizes rat brain membranes and is described by West et al., (xe2x80x9cIdentification of Two H3-Histamine Receptor Subtypesxe2x80x9d, Molecular Pharmacology, (1990), Vol. 33, 610-613. Several of the present compounds were found to have high H1 and H3 antagonist activity which is discussed more in the EXAMPLES section below.
In another embodiment, this invention provides pharmaceutical compositions comprising the above-described inventive imidazoles as an active ingredient. The pharmaceutical compositions generally additionally comprise a pharmaceutically acceptable carrier diluent, excipient or carrier (collectively referred to herein as carrier materials). Because of their H1 and H3 antagonist activity, such pharmaceutical compositions possess utility in treating allergy, inflammation, nasal congestion, hypertension, glaucoma, sleeping disorders, states of hypermotility of the gastrointestinal tract, and hyperactivity of the central nervous system, Alzheimers, Schizophrenia, migraines, obesity and the like diseases.
In yet another embodiment, the present invention discloses methods for preparing pharmaceutical compositions comprising the inventive imidazole compounds as an active ingredient. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e. oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Powders and tablets may be comprised of from about 5 to about 95 percent inventive composition.
Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate. Some of the terms noted above, namely disintegrants, diluents, lubricants, binders and the like, are discussed in more detail below.
Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects, i.e. antihistaminic activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injections or addition of sweeteners and pacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier such as inert compressed gas, e.g. nitrogen.
For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides such as cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein by stirring or similar mixing. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.
Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions may take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
The quantity of the inventive active composition in a unit dose of preparation may be generally varied or adjusted from about 1.0 milligram to about 1,000 milligrams, preferably from about 1.0 to about 950 milligrams, more preferably from about 1.0 to about 500 milligrams, and typically from about 1 to about 250 milligrams, according to the particular application. The actual dosage employed may be varied depending upon the patient""s age, sex, weight and severity of the condition being treated. Such techniques are well known to those skilled in the art.
Generally, the human oral dosage form containing the active ingredients can be administered 1 or 2 times per day. The amount and frequency of the administration will be regulated according to the judgment of the attending clinician. A generally recommended daily dosage regimen for oral administration may range from about 1.0 milligram to about 1,000 milligrams per day, in single or divided doses.
Capsulexe2x80x94refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active ingredients. Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
Tabletxe2x80x94refers to a compressed or molded solid dosage form containing the active ingredients with suitable diluents. The tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation or by compaction.
Oral gelsxe2x80x94refers to the active ingredients dispersed or solubilized in a hydrophillic semi-solid matrix.
Powders for constitution refers to powder blends containing the active ingredients and suitable diluents which can be suspended in water or juices.
Diluentxe2x80x94refers to substances that usually make up the major portion of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol; starches derived from wheat, corn, rice and potato; and celluloses such as microcrystalline cellulose. The amount of diluent in the composition can range from about 10 to about 90% by weight of the total composition, preferably from about 25 to about 75%, more preferably from about 30 to about 60% by weight, even more preferably from about 12 to about 60%.
Disintegrantsxe2x80x94refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments. Suitable disintegrants include starches; xe2x80x9ccold water solublexe2x80x9d modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures. The amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
Bindersxe2x80x94refers to substances that bind or xe2x80x9cgluexe2x80x9d powders together and make them cohesive by forming granules, thus serving as the xe2x80x9cadhesivexe2x80x9d in the formulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose and sodium carboxymethylcellulose and hydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics such as magnesium aluminum silicate. The amount of binder in the composition can range from about 2 to about 20% by weight of the composition, more preferably from about 3 to about 10% by weight, even more preferably from about 3 to about 6% by weight.
Lubricantxe2x80x94refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear. Suitable lubricants include metallic stearates such as magnesium stearate, calcium stearate or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d""l-leucine. Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press. The amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%, more preferably from about 0.3 to about 1.5% by weight.
Glidentsxe2x80x94materials that prevent caking and improve the flow characteristics of granulations, so that flow is smooth and uniform. Suitable glidents include silicon dioxide and talc. The amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
Coloring agentsxe2x80x94excipients that provide coloration to the composition or the dosage form. Such excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
Bioavailabilityxe2x80x94refers to the rate and extent to which the active drug ingredient or therapeutic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
Conventional methods for preparing tablets are known. Such methods include dry methods such as direct compression and compression of granulation produced by compaction, or wet methods or other special procedures. Conventional methods for making other forms for administration such as, for example, capsules, suppositories and the like are also well known.
Another embodiment of the invention discloses use of the pharmaceutical compositions disclosed above for treatment of diseases such as, for example, allergy, inflammation, nasal congestion, hypertension, glaucoma, sleeping disorders, states of hypermotility of the gastrointestinal tract, hyperactivity of the central nervous system, Alzheimers, Schizophrenia, migraines, obesity and the like. The method comprises administering a therapeutically effective amount of the inventive pharmaceutical composition to a mammalian patient having such a disease or diseases and in need of such a treatment.
Those skilled in the art will realize that the term xe2x80x9cupper airwayxe2x80x9d means the upper respiratory systemxe2x80x94i.e., the nose, throat, and associated structures.
It will be apparent to those skilled in the art that many modifications, variations and alterations to the present disclosure, both to materials and methods, may be practiced. Such modifications, variations and alterations are intended to be within the spirit and scope of the present invention.
The following EXAMPLES are being provided to further illustrate the present invention. They are for illustrative purposes only; the scope of the invention is not to be considered limited in any way thereby.